The present invention relates to novel oxyiminoalkanoic acid derivatives having hypoglycemic effect and hypolipidemic effect, a novel pharmaceutical composition and retinoid-related receptor function adjuster comprising an oxyiminoalkanoic acid. Such novel oxyiminoalkanoic acid derivatives, pharmaceutical compositions and retinoid-related receptor function adjusters are useful as an agent for prevention and/or treatment of diabetes mellitus, hyperlipemia, impaired glucose tolerance, inflammatory disease, arteriosclerosis and the like.
Examples of known oxyiminoalkanoic acid derivatives are the intermediates used in the production of xcex2-lactam compounds (Japanese Patent Application KOKAI No. 49382/1983, 167576/1984, 77391/1987, 192387/1987, 47186/1991) and a compound having a leukotriene biosynthesis inhibiting effect (e.g., WO96/02507).
However, these compounds have not been reported to have hypoglycemic, hypolipidemic effects and retinoid-related receptor function adjuster activity yet.
On the other hand, oxime derivatives were reported as a prophylactic and/or therapeutic agent against hyperlipemia and hyperglycemia (e.g., Japanese Patent Application KOKAI No. 48779/1997, 323929/1997), but these derivatives are not an oxyiminoalkanoic acid derivative.
Moreover, while a phenylalkanoyl acid derivative having a substituted hydroxyl group on its 4-position is reported (e.g. in WO97/31907, WO97/25042) as a peroxisome proliferator-activated receptor gamma (abbreviated occasionally as PPARxcex3 in this specification) agonist which is one of retinoid-related receptor function adjusters, this derivative is not an oxyiminoalkanoic acid derivative.
The peroxisome proliferator-activated receptor gamma (PPARxcex3) is a member of an intranuclear hormone receptor superfamily, representatives of which are a steroid hormone receptor and a thyroidal hormone receptor, and induced to be expressed at a very early stage of the fat cell differentiation, and plays an important role as a master regulator in the fat cell differentiation. PPARxcex3 is bound to a function adjuster to form a dimer with a retinoid X receptor (RXR), and is also bound to the responding site of a target gene in a nucleus, whereby regulating (activating) the transcription efficiency directly. Recently, a metabolite of prostaglandin D2, namely, 15-deoxy-xcex9412,14 prostaglandin J2, was proved to be an endogenous agonist of PPARxcex3, and some insulin sensitivity enhancing agent, such as a thiazolindione derivative, was proved to have a PPARxcex3 agonistic activity, with its potency being in parallel with its blood sugar reducing effect and fat cell differentiation promoting effect [Cell, Vol. 83, page 803 (1995); The Journal of Biological Chemistry, Vol. 270, page 12953 (1995); Journal of Medicinal Chemistry, Vol. 39, page 655 (1996)]. More recently, it has been shows that: 1) PPARxcex3 is expressed in a cultured, human fat sarcoma-derived cell, and its growth is terminated by addition of PPARxcex3 agonist [Proceedings of the National Academy of Science of The United States of America, Vol. 94, page 237 (1997)], 2) a non-steroid antiinflammatory agent such as indomethacin and phenoprofen has a PPARxcex3 agonistic activity [The Journal of Biological Chemistry, Vol. 272, page 3406 (1997)], 3) PPARxcex3 is highly expressed in an activated macrophage, and the addition of its agonist serves to inhibit the transcription of a gene concerned in an inflammation [Nature, Vol. 391, p.79 (1998)], and 4) a PPARxcex3 agonist inhibits the production of inflammatory cytokines (TNF xcex1, IL-1 xcex2, IL-6) by a monocyte [Nature, Vol. 391, page 82 (1998)].
The object of the present invention is to provide a novel oxyiminoalkanoic acid derivative and retinoid-related receptor function adjuster which has excellent hypoglycemic effect and hypolipidemic effect and which is useful as an agent for prevention and/or treatment of diabetes mellitus, hyperlipemia, impaired glucose tolerance, an inflammatory disease and an arteriosclerosis.
The present invention relates to:
1) a compound represented by Formula (I-1): 
xe2x80x83wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, xe2x80x94COxe2x80x94, xe2x80x94CH(OH)xe2x80x94 or a group represented by xe2x80x94NR6xe2x80x94 wherein R6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer of 1 to 3; Y is an oxygen atom, a sulfur atom, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or a group represented by xe2x80x94NR7xe2x80x94 wherein R7 is a hydrogen atom or an optionally substituted alkyl group; a ring A is a benzene ring optionally having additional one to three substituents; p is an integer of 1 to 8; R2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer of 0 to 6; m is 0 or 1; R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group.) or NR9R10 (R9 and R10 are the same or different groups which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group or R9 and R10 combine together to form a ring); R4 and R5 are the same or different groups which are selected from a hydrogen atom or an optionally substituted hydrocarbon group wherein R4 may form a ring with R2; provided that when R1 is a ethoxymethyl, a C1-3 alkyl, phenyl or p-methoxyphenyl and q=m=0, R3 is NR9R10; and provided that O-[2-chloro-4-(2-quinolylmethoxy)phenylmethyl]oxime of methyl pyruvate and [2-chloro-4-(2-quinolylmethoxy)phenylmethyl]-2-iminoxypropionic acid are excluded; or a salt thereof;
2) A compound of the above 1) wherein R1 is an optionally substituted heterocyclic group or an optionally substituted cyclic hydrocarbon group;
3) A compound of the above 1) wherein X is a bond or a group represented by xe2x80x94NR6xe2x80x94 wherein R6 is an optionally substituted alkyl group;
4) A compound of the above 1) wherein n is 1 or 2;
5) A compound of the above 1) wherein Y is an oxygen atom;
6) A compound of the above 1) wherein p is an integer of 1 to 3;
7) A compound of the above 1) wherein R3 is a hydroxy group or xe2x80x94OR8 or xe2x80x94NR9xe2x80x2R10xe2x80x2, wherein R8 is an optionally substituted hydrocarbon group and R9xe2x80x2 and R10xe2x80x2 are the same or different groups which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, or R9xe2x80x2 and R10xe2x80x2 combine together to form a ring;
8) A compound of the above 1) wherein q is an integer of 0 to 4;
9) A compound of the above 1) wherein R2 an optionally substituted hydrocarbon group;
10) A compound of E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid or its salt;
11) A compound which is selected from a group of E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyramide and E-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-8-phenyloctanoic acid;
12) A compound of the above 2) wherein a ring of an optionally substituted heterocyclic group or an optionally substituted cyclic hydrocarbon group of R1 is selected from the group represented by formulae of 
13) A compound of the above 12) wherein the ring optionally has one or two substituents which is selected from the group of an optionally substituted phenyl, an optionally substituted furyl, an optionally substituted thienyl and an optionally substituted C1-4 alkyl;
14) A compound of the above 12) wherein the ring is 
xe2x80x83wherein Ph is an optionally substituted phenyl group, and Rxe2x80x3 is a hydrogen or an optionally substituted C1-6 alkyl group;
15) A compound represented by Formula (I-2) of 
xe2x80x83wherein Rxe2x80x2 is an optionally substituted phenyl, furyl or thienyl group; Rxe2x80x3 is a hydrogen or a C1-6 alkyl which is optionally substituted by at least one selected from a group of a C1-6 alkoxy and a halogen; R2xe2x80x2 is a phenyl which is optionally substituted by at least one selected from a group of a hydrogen, an alkyl, an alkoxy and a halogen; q is an integer of 1 to 6; and R3xe2x80x2 is a hydroxy, a C1-6 alkoxy or xe2x80x94NR9R10 in which R9 and R10 are independently selected from the group of a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, or R9 and R10 combine together to form a ring; a ring A is a benzene ring optionally having additional one to three substituents; or a salt thereof;
16) A pharmaceutical composition comprising a compound represented by Formula (II) 
xe2x80x83wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, xe2x80x94COxe2x80x94, xe2x80x94CH(OH)xe2x80x94 or a group represented by xe2x80x94NR6xe2x80x94 wherein R6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer of 1 to 3; Y is an oxygen atom, a sulfur atom, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or a group represented by xe2x80x94NR7xe2x80x94 wherein R7 is a hydrogen atom or an optionally substituted alkyl group; ring A is a benzene ring optionally having additional one to three substituents; p is an integer of 1 to 8; R2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer of 0 to 6; m is 0 or 1; R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group.) or NR9R10 (R9 and R10 are the same or different groups which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group or R9 and R10 combine together to form a ring); R4 and R5 are the same or different groups which are selected from a hydrogen atom or an optionally substituted hydrocarbon group wherein R4 may form a ring with R2; or a salt thereof;
17) A pharmaceutical composition of the above 16) which is a composition for prevention or treatment of diabetes mellitus;
18) A pharmaceutical composition of the above 16) which is a composition for prevention or treatment of hyperlipemia;
19) A pharmaceutical composition of the above 16) which is a composition for prevention or treatment of impaired glucose tolerance;
20) A pharmaceutical composition of the above 16) which is a composition for prevention or treatment of an inflammatory disease; and
21) A pharmaceutical composition of the above 16) which is a composition for prevention or treatment of an arteriosclerosis.
22) An agent for controlling or adjusting retinoid-related receptor comprising a compound represented by Formula (II) of 
xe2x80x83wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, xe2x80x94COxe2x80x94, xe2x80x94CH(OH)xe2x80x94 or a group represented by xe2x80x94NR6xe2x80x94 wherein R6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer of 1 to 3; Y is an oxygen atom, a sulfur atom, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or a group represented by xe2x80x94NR7xe2x80x94 wherein R7 is a hydrogen atom or an optionally substituted alkyl group; ring A is a benzene ring optionally having additional one to three substituents; p is an integer of 1 to 8; R2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer of 0 to 6; m is 0 or 1; R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group.) or NR9R10 (R9 and R10 are the same or different groups which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group or R9 and R10 combine together to form a ring); R4 and R5 are the same or different groups which are selected from a hydrogen atom or an optionally substituted hydrocarbon group wherein R4 may form a ring with R2; or a salt thereof;
23) An agent of the above 22) which is a ligand of a peroxisome proliferator-activated receptors;
24) An agent of the above 22) which is a retinoid X receptor ligand;
25) An agent of the above 22) which is an insulin sensitivity enhancing agent;
26) An agent of the above 22) which is an insulin resistance improving agent;
(1) Definition of R1 
A hydrocarbon group in xe2x80x9can optionally substituted hydrocarbon groupxe2x80x9d represented by R1 in Formulae (I-1) and (II) includes an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an alicyclic-aliphatic hydrocarbon group, an aromatic-aliphatic hydrocarbon group and an aromatic hydrocarbon group. The number of the carbon atoms in each of these hydrocarbon group is preferably 1 to 14.
(1-1) Definition of Hydrocarbon Group for R1 
As the aliphatic hydrocarbon group, an aliphatic hydrocarbon group having 1 to 8 carbon atoms is preferred. Such aliphatic hydrocarbon group includes a saturated aliphatic hydrocarbon group having 1 to 8 carbon atoms (e.g., an alkyl group) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, octyl and the like; an unsaturated aliphatic hydrocarbon group having 2 to 8 carbon atoms (e.g., an alkenyl group, an alkadienyl group, an alkynyl group, an alkadiynyl group and the like) such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like.
As the alicyclic hydrocarbon group, an alicyclic hydrocarbon group having 3 to 7 carbon atoms is preferred. Such alicyclic hydrocarbon group includes a saturated alicyclic hydrocarbon group (e.g., a cycloalkyl group and the like) such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like; an unsaturated alicyclic hydrocarbon group (e.g., cycloalkenyl group, cycloalkadienyl group and the like) such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclpentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4-cycloheptadienyl and the like.
As the alicyclic-aliphatic hydrocarbon group, an alicyclic hydrocarbon group listed above attached to an aliphatic hydrocarbon group listed above (e.g., a cycloalkyl-alkyl group, a cycloalkenyl-alkyl group and the like) are exemplified, and an alicyclic-aliphatic hydrocarbon group having 4 to 9 carbon atom is preferred. Such alicyclic-aliphatic hydrocarbon group includes cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, cycloheptylethyl, and the like.
As the aromatic-aliphatic hydrocarbon group, an aromatic-aliphatic hydrocarbon group having 7 to 13 carbon atoms (e.g., an aralkyl group, an arylalkenyl group and the like) is preferred. Such araliphatic hydrocarbon group includes a phenylalkyl having 7 to 9 carbon atoms such as benzyl, phenethyl, 1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl and the like; a naphthylalkyl having 11 to 13 carbon atoms such as xcex1-naphthylmethyl, xcex1-naphthylethyl, xcex2-naphthylmethyl, xcex2-naphthylethyl and the like; a phenylalkenyl having 8 to 10 carbon atoms such as styryl and the like; a naphthylalkenyl having 12 to 13 carbon atoms such as 2-(2-naphthylvinyl) and the like.
As the aromatic hydrocarbon group, an aromatic hydrocarbon group having 6 to 14 carbon atoms (e.g., an aryl group and the like) is preferred. Such aromatic hydrocarbon group includes phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like, and, among these, those preferred are phenyl, 1-naphthyl, 2-naphthyl and the like.
(1-2) Definition of Heterocyclic Group for R1 
A heterocyclic group in xe2x80x9can optionally substituted heterocyclic groupxe2x80x9d represented by R1 in Formulae (I-1) and (II) includes a 5- to 7-membered monocyclic or condensed heterocyclic group having as its constituent atoms 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom in addition to carbon atoms. As the condensed heterocyclic ring, a 5- to 7-membered monocyclic heterocyclic ring condensed with a 6-membered ring containing 1 to 2 nitrogen atoms, with a benzene group, or with a 5-membered ring containing one sulfur atom may be exemplified.
Examples of the heterocyclic group are an aromatic heterocyclic group such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, isoxazolyl, isothiazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,3,4-thiaziazol-2-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, tetrazol-1-yl, tetrazol-5-yl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 2-quinazolyl, 4-quinazolyl, 2-quinoxalyl, 2-benzoxazolyl, 2-benzothiazolyl, benzimidazol-1-yl, benzimidazol-2-yl, indol-1-yl, indol-3-yl, 1H-indazol-3-yl, 1H-pyrrolo[2,3-b]pyrazin-2-yl, 1H-pyrrolo[2,3-b]pyridin-6-yl, 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl, 1H-imidazo[4,5-b]pyrazin-2-yl and the like as well as a non-aromatic heterocyclic group such as 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, 1-piperazinyl, 1-hexamethyleneiminyl, oxazolidin-3-yl, thiazolidin-3-yl, imidazolidin-3-yl, 2-oxoimidazolidin-1-yl, 2,4-dioxoimidazolidin-3-yl, 2,4-dioxooxazolidin-3-yl, 2,4-dioxothiazolidin-3-yl and the like.
A heterocyclic group is preferably pyridyl, oxazolyl, thiazolyl, benzoxazolyl or benzothiazolyl.
(1-3) Definition of Substituents of Hydrocarbon and/or Heterocyclic Group for R1 
Each of the hydrocarbon group and the heterocyclic group represented by R1 in Formulae (I-1) and (II) optionally have 1 to 5, preferably 1 to 3 substituents on its possible positions. Such substituents include an optionally substituted aliphatic hydrocarbon group, an optionally substituted alicyclic hydrocarbon group, an optionally substituted aromatic hydrocarbon group, an optionally substituted aromatic heterocyclic group, an optionally substituted non-aromatic heterocyclic group, a halogen atom, a nitro group, an optionally substituted amino group, an optionally substituted acyl group, an optionally substituted hydroxy group, an optionally substituted thiol group, an optionally esterified or amide-derivatized carboxyl group. The substituents represented by xe2x80x9coptionally substitutedxe2x80x9d are a C1-6 alkyl group, a C1-6 alkoxy group, a halogen (e.g., fluorine, chlorine, bromine, iodine and the like), nitro group, a C1-6 halo-alkyl group, a C1-6 halo-alkoxy group.
Examples of the aliphatic hydrocarbon group are a straight or branched aliphatic hydrocarbon group having 1 to 15 carbon atoms, such as an alkyl group, an alkenyl group, an alkynyl group and the like.
A preferred alkyl group includes an alkyl group having 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like.
A preferred alkenyl group includes an alkenyl group having 2 to 10 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like.
A preferred alkynyl group includes ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like.
As the alicyclic hydrocarbon group, a saturated or unsaturated alicyclic hydrocarbon group having 3 to 12 carbon atoms, such as a cycloalkyl group, a cycloalkenyl group, a cycloalkadienyl group, may be exemplified.
Preferred examples of the cycloalkyl group are a cycloalkyl group having 3 to 10 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.1.1]nonyl, bicyclo[4.2.1]nonyl, bicyclo[4.3.1]decyl and the like.
Preferred examples of the cycloalkenyl group are a cycloalkenyl group having 3 to 10 carbon atoms, such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like.
Preferred examples of the cycloalkanedienyl group are a cycloalkanedienyl group having 4 to 10 carbon atoms, such as 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like.
Preferred examples of the aromatic heterocyclic group are a 5- to 7-membered aromatic monocyclic group having as its constituent atoms 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom in addition to carbon atoms, such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl and the like; a bicyclic or tricyclic aromatic condensed heterocyclic ring having as its constituent atoms 1 to 5 hetero atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom in addition to carbon atoms, such as benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H -indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolyl, quinazolyl, quinoxalinyl, phthalazinyl, naphthylidinyl, purinyl, pteridinyl, carbazolyl, xcex1-carbonylyl, xcex2-carbonylyl, xcex3-carbonylyl, acridinyl, phenoxadinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, indolidinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl and the like.
Preferred examples of the non-aromatic heterocyclic group are oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, morpholino, thiomorpholino and the like.
Examples of the halogen atom are fluorine, chlorine, bromine and iodine, with fluorine and chlorine being preferred.
An optionally substituted amino group is an amino group optionally mono- or di-substituted with, for example, an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms, an acyl group having 3 to 10 carbon atoms (e.g., an alkanoyl group having 2 to 10 carbon atoms, an arylcarbonyl group having 7 to 13 carbon atoms and the like), or an aryl group having 6 to 12 carbon atoms. The acyl group has the same definition mentioned below for the acyl group in an optionally substituted acyl group.
The substituted amino group includes methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino, diallylamino, cyclohexylamino, acetylamino, propionylamino, benzoylamino, phenylamino, N-methyl-N-phenylamino and the like.
The acyl group in an optionally substituted acyl group is an acyl group having 1 to 13 carbon atoms, such as formyl, as well as a carbonyl group bound to an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms and an aromatic heterocyclic group (e.g., thienyl, furyl, pyridyl and the like).
Preferred examples of the acyl group are acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, oxtanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl, isonicotinoyl and the like.
Such acyl group optionally has one to three substituents on its possible positions, and such substituents include an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, halogen (e.g., fluorine, chlorine, iodine and the like), nitro, hydroxy, amino and the like.
Other types of acyl group are represented by a group of the formula: xe2x80x94COR11, xe2x80x94SO2R14, xe2x80x94SOR15 or xe2x80x94PO3R16R17 wherein R11, R14, R15, R16 and R17 are independently an optionally substituted hydrocarbon group.
Examples of the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R11, R14, R15, R16 and R17 are an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms.
The optionally substituted hydroxy group includes a hydroxy group, an alkoxy group, an alkenyloxy group, an aralkyloxy group, an acyloxy group, an aryloxy group and the like, each of which may optionally be substituted.
Preferred examples of the alkoxy group are an alkoxy group having 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
Preferred examples of the alkenyloxy group are an alkenyloxy group having 2 to 10 carbon atoms, such as allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, 2-cyclohexenylmethoxy and the like.
Preferred examples of the aralkyloxy group are an aralkyloxy group having 7 to 10 carbon atoms such as phenyl-C1-4 alkyloxy (e.g., benzyloxy, phenethyloxy and the like) and the like.
Preferred examples of the acyloxy group are an acyloxy group having 2 to 13 carbon atoms, preferably an alkanoyloxy having 2 to 4 carbon atoms (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy and the like) and the like.
Preferred examples of the aryloxy group are an aryloxy group having 6 to 14 carbon atoms such as phenoxy, naphthyloxy and the like.
Each of an alkoxy group, an alkenyloxy group, an aralkyloxy group, an acyloxy group and an aryloxy group described above may have 1 to 2 substituents on its possible positions, and such substituents include a halogen (e.g., fluorine, chlorine, bromine and the like), an alkoxy group having 1 to 3 carbon atoms. For example, a substituted aryloxy group may be 4-chlorophenoxy, 2-methoxyphenoxy and the like.
The optionally substituted thiol group includes a thiol, an alkylthio, a cycloalkylthio, an aralkylthio, an acylthio, an arylthio, a heteroarylthio and the like.
Preferred examples of the alkylthio group are an alkylthio group having 1 to 19 carbon atoms such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, t-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, nonylthio and the like.
Preferred examples of the cycloalkylthio group are a cycloalkylthio group having 3 to 10 carbon atoms such as cyclobutylthio, cyclopentylthio, cyclohexylthio and the like.
Preferred examples of the aralkylthio group are an aralkylthio group having 7 to 10 carbon atoms such as phenyl-C1-4 alkylthio (e.g., benzylthio, phenethylthio and the like) and the like.
Preferred examples of the acylthio group are an acylthio group having 2 to 13 carbon atoms, preferably an alkanoylthio group having 2 to 4 carbon atoms (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio and the like) and the like.
Preferred examples of the arylthio group are an arylthio group having 6 to 14 carbon atoms, such as phenylthio, naphthylthio and the like.
Preferred examples of the heteroarylthio group are 2-pyridylthio, 3-pyridylthio as well as 2-imidazolylthio, 1,2,4-triazol-5-ylthio and the like.
The optionally esterified carboxyl group includes a carboxyl group, an alkoxycarbonyl group having 2 to 5 carbon atoms (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like), an aralkyloxycarbonyl group having 8 to 10 carbon atoms (e.g., benzyolxycarbonyl and the like), an aryloxycarbonyl group having 7 to 15 carbon atoms optionally substituted with one or two alkyl groups having 1 to 3 carbon atoms (e.g., phenoxycarbonyl, p-tolyloxycarbonyl and the like) and the like.
The optionally substituted amide-derived carboxyl group includes a group represented by Formula: xe2x80x94CON(R12)(R13) wherein R12 and R13 may be same or different and is hydrogen, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group.
The hydrocarbon group and the heterocyclic group in xe2x80x9can optionally substituted hydrocarbon groupxe2x80x9d and xe2x80x9can optionally substituted heterocyclic groupxe2x80x9d represented by R12 and R13 includes an aliphatic hydrocarbon group, an alicyclic hydrocarbon group and an aromatic and heterocyclic group exemplified as the same described in the above (1-1) and (1-2), respectively. Such hydrocarbon groups optionally have 1 to 3 substituents on its possible positions, and such substituents include a halogen (e.g., fluorine, chlorine, bromine, iodine and the like), an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms and the like.
A substituent in the hydrocarbon group and the heterocyclic group represented by R1 in Formulae (I-1) and (II) is preferably an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 1 to 10 carbon atoms, an aromatic heterocyclic group, an aryl group having 6 to 14 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, furyl, thienyl, phenyl and naphthyl.
The substituent in the hydrocarbon group and the heterocyclic group represented by R1, when it is an alicyclic hydrocarbon group, an aromatic hydrocarbon group, an aromatic heterocyclic group or a non-aromatic heterocyclic group, optionally have one or more, preferably 1 to 3 appropriate substituents, and such substituents include an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an aryl group having 6 to 14 carbon atoms (e.g., phenyl, naphthyl and the like), an aromatic heterocyclic group (e.g., thienyl, furyl, pyridyl, oxazolyl, thiazolyl and the like), a non-aromatic heterocyclic group (e.g., tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidinyl, piperazinyl and the like), an aralkyl group having 7 to 9 carbon atoms, amino group, an amino group mono- or di-substituted with an alkyl group having 1 to 4 carbon atoms or with an acyl group having 2 to 8 carbon atoms (e.g., an alkanoyl group and the like), an amidino group, an acyl group having 2 to 8 carbon atoms (e.g., alkanoyl group and the like), carbamoyl group, a carbamoyl group mono- or di-substituted with an alkyl group having 1 to 4 carbon atoms, sulfamoyl group, a sulfamoyl group mono- or di-substituted with an alkyl group having 1 to 4 carbon atoms, carboxyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms, hydroxy group, an alkoxy group having 1 to 6 carbon atoms, an alkenyloxy group having 2 to 5 carbon atoms, a cycloalkyloxy group having 3 to 7 carbon atoms, an aralkyloxy group having 7 to 9 carbon atoms, an aryloxy group having 6 to 14 carbon atoms (e.g., phenyloxy, naphthyloxy and the like), thiol group, an alkylthio group having 1 to 6 carbon atoms, an aralkylthio group having 7 to 9 carbon atoms, an arylthio group having 6 to 14 carbon atoms (e.g., phenylthio, naphthylthio and the like), sulfonyl group, cyano group, azide group, nitro group, nitroso group, a halogen atom (e.g., fluorine chlorine, bromine, iodine) and the like.
(1-4) Preferred Examples of R1 
R1 in Formulae (I-I) and (II) is preferably an optionally substituted heterocyclic group, and more preferably pyridyl, oxazolyl, thiazolyl or triazolyl each of which is optionally substituted. A particularly preferable R1 is pyridyl, oxazolyl, thiazolyl or triazolyl which optionally have 1 to 2 substituents selected from the group consisting of an alkyl having 1 to 3 carbon atoms a cycloalkyl having 3 to 7 carbon atoms, furyl, thienyl, phenyl and naphthyl. The furyl, thienyl, phenyl and naphthyl optionally have substituents selected from an alkyl having 1 to 3 carbon atoms, an alkoxy having 1 to 3 carbon atoms, a halogen (e.g., fluorine, chlorine, bromine, iodine and the like) and halo-alkyl having 1 to 3 carbon atoms.
Such preferred ring of an optionally substituted heterocyclic group or an optionally substituted cyclic hydrocarbon group of R1 is selected from the group represented by formulae of 
The ring optionally has one or two substituents which is selected from the group of a phenyl, a furyl, a thienyl and a C1-4 alkyl. The group of a phenyl, a furyl and a thienyl optionally have substituents selected from C1-6 alkyl group, C1-6 alkoxy group, a halogen (e.g., fluorine, chlorine, bromine, iodine and the like), nitro group, C1-6 halo-alkyl group, C1-6 halo-alkoxy group.
Further preferred one for R1 is a formula of 
wherein Ph is an optionally substituted phenyl group, and Rxe2x80x3 is a hydrogen or an optionally substituted C1-6 alkyl group.
The substituents of Ph and the C1-6 alkyl group of Rxe2x80x3 are a C1-6 alkoxy group, a halogen (e.g., fluorine, chlorine, bromine, iodine and the like), a nitro group, a C1-6 halo-alkyl group or a C1-6 halo-alkoxy group.
(2) Definition of X
In Formulae (I-1), (I-2) and (II) X is a bond, xe2x80x94COxe2x80x94, xe2x80x94CH(OH)xe2x80x94 or a group represented by xe2x80x94NR6xe2x80x94 wherein R6 hydrogen, is an optionally substituted alkyl group, with a bond, xe2x80x94CH(OH)xe2x80x94 or xe2x80x94NR6xe2x80x94 being preferred and a bond or xe2x80x94NR6xe2x80x94 being more preferred.
An alkyl group in xe2x80x9can optionally substituted alkyl groupxe2x80x9d represented by R6 includes an alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl and the like. Such alkyl group optionally have 1 to 3 substituents on its possible positions, and such substituents include a halogen (fluorine, chlorine, bromine, iodine), an alkoxy group having 1 to 4 carbon atoms (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy and the like), hydroxy group, nitro group, an acyl group having 1 to 4 carbon atoms (e.g., an alkanoyl group having 1 to 4 carbon atoms such as formyl, acetyl, propionyl and the like).
(3) Definition of n and Y
In Formulae (I-1), (I-2) and (II), n is an integer of 1 to 3, preferably 1 to 2.
In Formulae (I-1), (I-2) and (II), Y is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or xe2x80x94NR7xe2x80x94 wherein R7 is an hydrogen optionally substituted alkyl group, with xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR7xe2x80x94 being preferred. xe2x80x9cAn optionally substituted alkyl groupxe2x80x9d represented by R7 includes those exemplified as xe2x80x9can optionally substituted alkyl groupxe2x80x9d represented by R6 described above.
(4) Definition of Ring A
Ring A in Formulae (I-1), (I-2) and (II) represents a benzene ring, and optionally has additional 1 to 3 substituents on its possible positions. Such substituents include an alkyl group, an optionally substituted hydroxy group, a halogen atom, an optionally substituted acyl group, nitro group, and an optionally substituted amino group, each of which is exemplified as a substituent on a hydrocarbon group and a heterocyclic group represented by R1.
Such substituent is preferably an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or a halogen atom. The ring A is preferably a non-substituted benzene ring.
In Formulae (I-1), and (II), a moiety: 
(5) Definition of P
In Formulae (I-1), (I-2) and (II), p is an integer of 1 to 8, preferably an integer of 1 to 3.
(6) Definition of R2 
In Formulae (I-1), (I-2) and (II), xe2x80x9can optionally substituted hydrocarbon groupxe2x80x9d represented by R2 may be one exemplified as xe2x80x9can optionally substituted hydrocarbon groupxe2x80x9d represented by R1.
xe2x80x9cAn optionally substituted heterocyclic groupxe2x80x9d represented by R2 may be one exemplified as xe2x80x9can optionally substituted heterocyclic groupxe2x80x9d represented by R1.
In Formulae (I-1), (I-2) and (II), R2 is preferably an optionally substituted hydrocarbon group. More preferably, R2 is an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aromatic-aliphatic hydrocarbon group or an aromatic hydrocarbon group each of which is optionally substituted, and particularly preferred is an alkyl group having 1 to 4 carbon atoms, a phenylalkyl group having 8 to 10 carbon atoms, an aryl group having 6 to 14 carbon atoms, each of which is optionally substituted.
A substituent which is optionally present on each of the hydrocarbon groups described above is preferably a halogen atom, an alkoxy group having 1 to 4 carbon atoms, an aryloxy group having 6 to 14 carbon atoms and an aromatic heterocyclic group (e.g., furyl, thienyl).
(7) Definition of q, and m
In Formulae (I-1) and (I-2), q is an integer of 0 to 6, preferably 0 to 4. m is 0 or 1. In Formulae (I-1) where R1 is ethoxymethyl, a C1-3 alkyl, phenyl or p-methoxyphenyl, q is an integer of 1 to 6.
In Formulae (II), q is an integer of 0 to 6, preferably 0 to 4. m is 0 or 1.
(8) Definition of R3 
R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group.) or NR9R10 (R9 and R10 are the same or different groups which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group or R9 and R10 combine together to form a ring).
In Formulae (I-1), (I-2) and (II), xe2x80x9can optionally substituted hydrocarbon groupxe2x80x9d represented by R8 includes one exemplified as xe2x80x9can optionally substituted hydrocarbon groupxe2x80x9d represented by R1. A particularly preferred R3 is hydroxy group.
In Formulae (I-1), (I-2) and (II), xe2x80x9can optionally substituted hydrocarbon groupxe2x80x9d represented by R9 and R10 includes one exemplified as xe2x80x9can optionally substituted hydrocarbon groupxe2x80x9d represented by R1.
In Formulae (I-1), (I-2) and (II), xe2x80x9can optionally substituted heterocyclic groupxe2x80x9d represented by R9 and R10 includes one exemplified as xe2x80x9can optionally substituted heterocyclic groupxe2x80x9d represented by R1.
In Formulae (I-1), (I-2) and (II), xe2x80x9can optionally substituted acyl groupxe2x80x9d represented by R9 and R10 includes one exemplified as xe2x80x9can optionally substituted acyl groupxe2x80x9d represented by R1.
In Formulae (I-1), (I-2) and (II), R9 and R10 optionally combine together to form a ring such as 1-pyrrolidinyl, 1-piperidinyl, 1-hexamethyleneiminyl, 4-morpholino, 4-thiomorpholino.
(9) Definition of R4 and R5 
xe2x80x9cAn optionally substituted alkyl groupxe2x80x9d represented by R4 and R5 in Formulae (I-1), and (II) includes the same as xe2x80x9can optionally substituted alkyl groupxe2x80x9d represented by R6 described above.
xe2x80x9cAn optionally substituted hydrocarbon groupxe2x80x9d and xe2x80x9can optionally substituted heterocyclic groupxe2x80x9d represented by R9 and R10 in Formulae (I-1), (I-2) and (II) includes the same as xe2x80x9can optionally substituted hydrocarbon groupxe2x80x9d and xe2x80x9can optionally substituted heterocyclic groupxe2x80x9d represented by R12 and R13, respectively, described above.
xe2x80x9cAn optionally substituted hydrocarbon groupxe2x80x9d represented by R11 in Formulae (I-1), (I-2) and (II) includes an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms optionally substituted with an alkyl group having 1 to 4 carbon atoms or with a halogen atom. Such alkyl group having 1 to 4 carbon atoms in xe2x80x9can alkyl group having 1 to 4 carbon atomsxe2x80x9d and xe2x80x9can aryl group having 6 to 10 carbon atoms optionally substituted with an alkyl group having 1 to 4 carbon atoms or with a halogen atomxe2x80x9d represented by R8 includes methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, t-butyl and the like, with methyl and ethyl being preferred. A halogen in xe2x80x9can aryl group having 6 to 10 carbon atoms optionally substituted with an alkyl group having 1 to 4 carbon atoms or with a halogen atomxe2x80x9d includes fluorine, chlorine, bromine, iodine and the like, with chlorine being preferred, and an aryl group having 6 to 10 carbon atoms may include phenyl and naphthyl, with phenyl being preferred.
(10) E-form and/or Z-form Compound
A compound represented by Formulae (I-1), (I-2) and (II) is present in E- and Z-isomers with regard to the imino bond. Said compound may be either single one of E- or Z-form, or may be the mixture of the two.
O-[2-chloro-4-(2-quinolylmethoxy)phenylmethyl]oxime of methyl pyruvate and [2-chloro-4-(2-quinolylmethoxy)phenylmethyl]-2-iminoxy propionic acid are known compounds disclosed in WO96/02507, and excluded from Formula (I-1).
(11) Preferred Embodiments
Among the compounds of Formula (I-1), one of the preferred embodiments of the present invention is a compound represented by the formula of 
wherein Rxe2x80x2 is a phenyl, furyl or thienyl which optionally has substituents selected from a C1-6 alkyl group, a C1-6 alkoxy group, a halogen (e.g., fluorine, chlorine, bromine, iodine and the like), nitro group, a C1-6 halo-alkyl group, a C1-6 halo-alkoxy group; Rxe2x80x3 is a hydrogen or an optionally substituted C1-6 alkyl (more preferably a hydrogen, methyl or ethyl); R2xe2x80x2 is a phenyl which is optionally substituted by at least one substituent selected from a group of a hydrogen, a C1-6 alkyl, a C1-6 alkoxy and a halogen; q is an integer of 1 to 6; and R3xe2x80x2 is a hydroxy, a C1-6 alkoxy or xe2x80x94NR9R10 in which R9 and R10 are independently selected from the group of a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, or R9 and R10 combine together to form a ring; a ring A is an optionally substituted benzene ring; or a salt thereof.
Another preferred embodiment of the present invention is a compound represented by a formula of 
wherein each symbol has the same definition mentioned above; or a salt thereof.
Preferred specific examples of the compound represented by Formulae (I-1), (I-2) and (II) are Compound (1) to (10) listed below.
(1) Z-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-phenylacetic acid
(2) Z-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid
(3) Z-2-(4-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetic acid
(4) Z-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(4-phenoxyphenyl)acetic acid
(5) Z-4-(4-fluorophenyl)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyric acid
(6) Z-3-methyl-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyric acid
(7) E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid
(8) E-4-(4-fluorophenyl)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyric acid
(9) E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyamide
(10) E-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-8-phenyloctanoic acid
These compounds may hereinafter be abbreviated as Compound (1), Compound (2) or the like.
(12) Examples of Salts
A salt of a compound represented by Formula (I-1), (I-2) or (II) (which may hereinafter be abbreviated as Compound (I-1), (I-2) or (II)) is preferably a pharmacologically acceptable salt, such as a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic salt, a salt with a basic or acidic amino acid and the like.
Preferred examples of the salt with an inorganic base are an alkali metal salt such as a sodium salt and a potassium salt; an alkaline earth metal salt such as a magnesium salt; as well as an aluminum salt and an ammonium salt and the like.
Preferred examples of the salt with an organic base are salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N-dibenzylethylenediamine and the like.
Preferred examples of the salt with an inorganic acid are salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
Preferred examples of the salt with an organic acid are salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
Preferred examples of the salt with a basic amino acid are salts with arginine, lysine, ornithine and the like, while preferred examples of a salt with an acidic amino acid are salts with aspartic acid, glutamic acid and the like.
Among the salts described above, those preferred are sodium salts, potassium salts, hydrochlorides and the like.
(13) Formulation
A compound represented by Formula (I-1), (I-2) or (II) and a salt thereof (which may hereinafter be abbreviated as a compound according to the present invention) has a low toxicity, and can be formulated together with a pharmacologically acceptable carrier into a pharmaceutical composition, which may be used as an agent for prevention and/or treatment of various diseases discussed below in mammals (e.g., human, mouse, rat, rabbit, dog, cat, cattle, horse, swine, monkey and the like).
The pharmacologically acceptable carrier employed here is selected from various customary organic or inorganic materials used as materials for pharmaceutical formulations, and may be incorporated as excipients, glidants, binders and disintegrants in a solid formulation; vehicles, solubilizers, suspending agents, tonicity agents, buffer, analgesic agents in a liquid formulation. If necessary, pharmaceutical additives such as preservatives, antioxidants, colorants, sweeteners may also be added.
Preferred examples of the excipients are lactose, sugar, D-mannitol, D-sorbitol, starch, xcex1-starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light silicic anhydride, synthetic aluminum silicate, magnesium aluminate metasilicate and the like.
Preferred examples of the glidants are magnesium stearate, calcium stearate, talc, colloidal silica and the like.
Preferred examples of the binders are xcex1-starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sugar, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like.
Preferred examples of the disintegrants are sugar, starch, carboxymethylcellulose, potassium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, light silicic anhydride, low-substituted hydroxypropylcellulose and the like.
Preferred examples of the vehicles are water for injection, physiological saline, Ringer""s solution, alcohols, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cotton seed oil and the like.
Preferred examples of the solubilizers are polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate and the like.
Preferred examples of the suspending agents are a surfactant such as stearyltriethanolamine, sodium laurylsulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate and the like; a hydrophilic polymer such as polyvinylalcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like; and polysorbates, polyoxyethylene hydrogenated castor oil and the like.
Preferred examples of the tonicity agents are sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like.
Preferred examples of the buffer solution are the solutions of phosphates, acetates, carbonates, citrates and the like.
Preferred examples of the analgesic agents includes benzylalcohol and the like.
Preferred examples of the preservatives are p-oxybenzoates, chlorobutanol, benzylalcohol, phenethylalcohol, dehydroacetic acid, sorbic acid and the like.
Preferred examples of the antioxidants are sulfites, ascorbates and the like.
Preferred examples of the colorants are a water soluble tar pigments (e.g., edible pigments such as edible color Red No.2 and No.3, edible color Yellow No.4 and No.5, edible color Blue No.1 and No.2), a water-insoluble lake pigments (e.g., aluminum salts of the water soluble edible tar pigments listed above and the like), a natural pigment (e.g., xcex2-carotene, chlorophyll, iron oxide red and the like) and the like.
Preferred examples of the sweeteners are saccharin sodium, potassium glycyrrhizinate, Aspartame, steviocides and the like.
(14) Dosage Form
A dosage form of a pharmaceutical composition includes an oral formulation such as a capsule (including a soft capsule and a microcapsule), a granule, a powder, a syrup, an emulsion, a suspension and the like; a non-oral formulation such as a formulation for injection (e.g., subcutaneous injection formulation, intravenous injection formulation, intramuscular injection formulation, intraperitoneal injection formulation and the like), a formulation for drip infusion, a formulation for external application (e.g., nasal formulation, percutaneous formulation, ointments and the like), a suppository (e.g., rectal suppository, vaginal suppository and the like), a pellet, a formulation for drip infusion and the like, all of which can safely be given via an oral or a non-oral route.
The pharmaceutical composition may be produced by a conventional method in the field of pharmaceutical technology, for example, a method described in Japanese Pharmacopoeia. A method for producing a formulation is described in detail below.
An oral formulation is, for example, prepared by admixing an active ingredient with an excipient (e.g., lactose, sugar, starch, D-mannitol and the like), a disintegrant (e.g., calcium carboxymethylcellulose and the like), a binder (e.g., xcex1 starch, gum arabic, carboxymethylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone and the like), or a glidant (e.g., talc, magnesium stearate, polyethylene glycol 6000 and the like), followed by compaction molding, further followed, if necessary, by coating with a coating base by a known method for the purpose of masking a taste, obtaining an enteric dissolution or a sustained release.
Such coating base includes a sugar coating base, a water soluble film coating base, an enteric coating base, a sustained release film coating base and the like.
A sugar coating base includes a sugar, which may be used in combination with one or more materials selected from the group consisting of talc, sedimentation calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like.
A water soluble film coating base includes a cellulose-based polymer such as hydroxpropylcellulose, hydroxypropylmethylcellulose, methylhydroxyethylcellulose and the like; a synthetic polymer such as polyvinylacetal diethylaminoacetate, aminoalkylmethacrylate copolymer E [Eudragit E (trade name), Rohm Pharma], polyvinylpyrrolidone and the like; and a polysaccharide such as pullulan.
An enteric film coating base includes a cellulose-based polymer such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate and the like; an acrylic acid-based polymer such as methacrylic acid copolymer L [Eudragit L (trade name), Rxc3x6hm Pharma], methacrylic acid copolymer LD [Eudragit L-30D55 (trade name), Rxc3x6hm Pharma], methacrylic acid copolymer S [Eudragit S (trade name), Rxc3x6hm Pharma] and the like; a naturally-occurring material such as shellac.
A sustained release film coating base includes a cellulose-based polymer such as ethylcellulose; an acrylic acid-based polymer such as aminoalkylmethacrylate copolymer RS [Eudragit RS (trade name), Rxc3x6hm Pharma], ethylacrylatemethylmethacrylate copolymer suspension [Eudragit NE (trade name), Rxc3x6hm Pharma] and the like.
A mixture of two or more coating bases described above may also be employed in a certain appropriate ratio. A light-shielding material such as titanium oxide and iron dioxide or trioxide may also be employed in the coating.
An injection formulation may be prepared by dissolving, suspending or emulsifying an an active ingredient together with a dispersant (e.g., polysorbate 80, polyoxyethylene hydrogenated castor oil 60 and the like), polyethylene glycol, carboxymethylcellulose, sodium alginate and the like, a preservative (e.g., methylparaben, propylparaben, benzylalcohol, chlorobutanol, phenol and the like), a tonicity agent (e.g., sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like) and the like, in an aqueous solvent (e.g., distilled water, physiological saline, Ringer""s solution and the like) or a lipophilic solvent (e.g., a vegetable oil such as olive oil, sesame oil, cotton seed oil, corn oil and the like or propylene glycol). In this procedure, an additive such as a solubilizer (e.g. sodium salicylate, sodium acetate and the like), a stabilizer (e.g., human serum albumin and the like), an analgesic agent (e.g., benzylalcohol and the like) may also be employed if necessary.
(15) Composition
The other aspect of the present invention is a pharmaceutical composition comprising a compound represented by Formula (II) 
wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, xe2x80x94COxe2x80x94, xe2x80x94CH(OH)xe2x80x94 or a group represented by xe2x80x94NR6xe2x80x94 wherein R6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer of 1 to 3; Y is an oxygen atom, a sulfur atom, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or a group represented by xe2x80x94NR7xe2x80x94 wherein R7 is a hydrogen atom or an optionally substituted alkyl group; ring A is a benzene ring optionally having additional one to three substituents; p is an integer of 1 to 8; R2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer of 0 to 6; m is 0 or 1; R3 is a hydroxy group, OR8 (R8 is an optionally substituted hydrocarbon group.) or NR9R10 (R9 and R10 are the same or different groups which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group or R9 and R10 combine together to form a ring); R4 and R5 are the same or different groups which are selected from a hydrogen atom or an optionally substituted hydrocarbon group wherein R4 may form a ring with R2; or a salt thereof. Each above-mentioned substituent has the same detailed definition of the corresponding one defined for Formula (I-1).
Especially, the pharmaceutical composition can be used for prevention or treatment of diseases such as diabetes mellitus, hyperlipemia, impaired glucose tolerance, an inflammatory disease, an arteriosclerosis and the like.
Among these compositions, a preferred one is a composition a compound represented by a formula of 
wherein Rxe2x80x2 is a phenyl, furyl or thienyl which optionally has substituents selected from a C1-6 alkyl group, a C1-6 alkoxy group, a halogen (e.g., fluorine, chlorine, bromine, iodine and the like), nitro group, a C1-6 halo-alkyl group, a C1-6 halo-alkoxy group; Rxe2x80x3 is a hydrogen or a C1-6 alkyl (more preferably, a hydrogen, methyl or ethyl) ; R2xe2x80x2 is a phenyl which is optionally substituted by at least one selected from a group of a hydrogen, a C1-6 alkyl, a C1-6 alkoxy and a halogen; q is an integer of 1 to 6; and R3xe2x80x2 is a hydroxy, an alkoxy or xe2x80x94NR9R10 in which R9 and R10 are independently selected from the group of a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, or R9 and R10 combine together to form a ring; a ring A is an optionally substituted benzene ring; or a salt thereof.
Another preferred composition of the present invention is a composition comprising a compound represented by a formula of 
wherein each symbol has the same definition mentioned above; or a salt thereof.
(16) Agent
According to the useful function of the compound of the present invention, the compound can be used as an insulin sensitivity enhancing agent; an insulin resistance improving agent; an agent for controlling or adjusting retinoid-related receptor; a ligand of a peroxisome proliferator-activated receptors; a retinoid X receptor ligand; etc.
A compound according to the present invention has a blood sugar reducing effect, a blood lipid reducing effect, a blood insulin reducing effect, an insulin sensitivity enhancing effect, an insulin resistance improving effect and retinoid-related receptor function adjuster activities. A retinoid-related receptor used here is encompassed in nuclear receptors, and is a DNA-binding transcription factor having as a function adjuster a signal molecule such as an oil-soluble vitamin, and may be any of a monomer receptor, a homodimer receptor and a heterodimer receptor.
A monomer receptor is exemplified by retinoid O receptor (hereinafter abbreviated occasionally as ROR) xcex1 (GenBank Accession No.L14611), RORxcex2 (GenBank Accession No.L14160), RORxcex3 (GenBank Accession No.U16997); Rev-erbxcex1 (GenBank Accession No.M24898), Rev-erbxcex2 (GenBank Accession No.L31785); ERRxcex1 (GenBank Accession No.X51416), ERRxcex2 (GenBank Accession No.X51417); Ftz-FIxcex1 (GenBank Accession No.S65876), Ftz-FIxcex2 (GenBank Accession No.M81385); TIx (GenBank Accession No.S77482); GCNF (GenBank Accession No.U14666) and the like.
A homodimer receptor may for example be a homodimer formed from retinoid X receptor (hereinafter abbreviated occasionally as RXR) xcex1 (GenBank Accession No.X52773), RXRxcex2 (GenBank Accession No.M84820), RXRxcex3 (GenBank Accession No.U38480); COUPxcex1 (GenBank Accession No.X12795), COUPxcex2 (GenBank Accession No.M64497), COUPxcex3 (GenBank Accession No.X12794); TR2xcex1 (GenBank Accession No.M29960), TR2xcex2 (GenBank Accession No.L27586); or, HNF4xcex1 (GenBank Accession No.X76930), HNF4xcex3 (GenBank Accession No.Z49826) and the like.
A heterodimer receptor may for example be a heterodimer formed from retinoid receptor X (RXRxcex1, RXRxcex2 or RXRxcex3) described above together with one receptor selected from the group consisting of retinoid A receptor (hereinafter abbreviated occasionally as RAR) xcex1 (GenBank Accession No.X06614), RARxcex2 (GenBank Accession No.Y00291), RARxcex3 (GenBank Accession No.M24857); a thyroidal hormone receptor (hereinafter abbreviated occasionally as TR) xcex1 (GenBank Accession No.M24748), TRxcex2 (GenBank Accession No.M26747); a vitamin D receptor (VDR) (GenBank Accession No.J03258); a peroxisome proliferator-activated receptor (hereinafter abbreviated occasionally as PPAR) xcex1 (GenBank Accession No.L02932), PPARxcex2 (PPAR xcex4) (GenBank Accession No.U10375), PPARxcex3 (GenBank Accession No.L40904); IXRxcex1 (GenBank Accession No.U22662), LXRxcex2 (GenBank Accession No.U14534); FXR (GenBank Accession No.U18374); MB67 (GenBank Accession No.L29263); ONR (GenBank Accession No.X75163; and NURxcex1 (GenBank Accession No.L13740), NURxcex2 (GenBank Accession No.X75918), NURxcex3 (GenBank Accession No.U12767).
Compound (I-2) and its salts exhibit excellent function adjuster activity especially toward retinoid X receptors (RXRxcex1, RXRxcex2, RXRxcex3) and peroxisome proliferator-activated receptors (PPARxcex1, PPARxcex2 ((PPAR xcex4), PPARxcex3) among those retinoid-related receptors listed above.
In addition Compound (II) or its salts exhibit excellent ligand activity toward a heterodimer receptor formed from a retinoid X receptor and a peroxisome proliferator-activated receptor, preferably a peroxisome proliferator-activate receptor as in the heterodimer receptor formed from RXRxcex1 and PPARxcex3.
Accordingly, a retinoid-related receptor function adjuster according to the present invention is used advantageously as a peroxisome proliferator-activate receptor ligand or a retinoid X receptor ligand.
(17) Diseases to be Treated
Accordingly, a compound or a pharmaceutical composition according to the present invention can be used for the prevention or treatment of diabetes mellitus (e.g., insulin-dependent diabetes mellitus(type-1 diabetes mellitus), non-insulin-dependent diabetes mellitus(type-2 diabetes mellitus), pregnancy diabetes mellitus and the like), hyperlipemia (e.g., hypertriglycemia, hypercholesterolemia, hypoHDLemia and the like), insulin insensitivity, insulin resistance, and impaired glucose tolerance (IGT).
A compound or a pharmaceutical composition according to the present invention may also be used for the prevention or treatment of diabetic complications (e.g., neuropathy, nephropathy, retinopathy, cataract, large blood vessel disorders, osteopenia and the like), obesity, osteoporosis, cachexia (e.g., carcinomatous cachexia, tuberculous cachexia, diabetic cachexia, hemophathic cachexia, endocrinopathic cachexia, infectious cachexia or cachexia induced by acquired immunodeficiency syndrome), fatty liver, hypertension, polycystic ovary syndrome, renal disorders (e.g., glomerular nephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, terminal renal disorders and the like), muscular dystrophy, myocardiac infarction, angina pectoris, cerebral infarction, insulin resistance syndrome, syndrome X, hyperinsulinemia-induced sensory disorder, tumors (e.g., leukemia, breast cancer, prostate cancer, skin cancer and the like), inflammatory diseases (e.g., rheumatoid arthritis, spondylitis deformans, osteoarthritis, lumbago, gout, surgical wound inflammation and swelling remedy, neuralgia, pharyngolaryngitis, cystitis, hepatitis, pneumonia, pancreatitis and the like), arterial sclerosis (e.g., atherosclerosis and the like).
A compound according to the invention may also be employed as a pharmaceutical for controlling appetite, food intake, diet and anorexia.
While the dose of a compound or a pharmaceutical composition according to the present invention varies depending on various factors such as the subject to be treated, the administration route, the disease or the condition to be treated, a compound according to the present invention as an active ingredient may for example be given orally to an adult at a single dose of about 0.05 to 100 mg/kg body weight, preferably about 0.1 to 10 mg/kg body weight, preferably one to three times a day.
(18) Combination Use of Drugs
A compound according to the present invention may be used in combination with a diabetes mellitus-treating agent, a diabetic complication-treating agent, an antihyperlipemic agent, a hypotensive agent, an anti-obesity agent, a diuretic, a chemotherapeutic agent, an immunotherapeutic agent and the like (hereinafter referred to as a concomitant agent). In such case, the periods of the treatments with a compound according to the present invention and with a concomitant agent are not limited particularly, and such agents may given to a patient simultaneously or at a certain time interval. The dose of a concomitant drug may appropriately be determined based on the customary clinical dose. The ratio between a compound according to the present invention and a concomitant agent may be appropriately determined based on various factors such as the subject to be treated, the administration route, the disease or the condition to be treated and the combination of the drugs. For example, when a human is treated, 1 parts by weight of a compound according to the present invention is combined with 0.01 to 100 parts by weight of a concomitant agent.
Examples of an agent for treating diabetes mellitus are an insulin formulation (e.g., animal insulin formulations extracted from a pancreas of a cattle or a swine; a human insulin formulation synthesized by a gene engineering technology using colibacillus and yeasts), an insulin sensitivity enhancing agent (e.g., pioglitazone hydrochloride, troglitazone, rosiglitazone and the like), an xcex1-glycosidase inhibitor (e.g., voglibose, acarbose, miglitol, emiglitate and the like), a Biguanide (e.g., phenformin, metoformin, buformin and the like), or a sulfonylurea (e.g., tolbutamide, glibenclamid, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride and the like) as well as other insulin secretion-promoting agents (e.g., repaglinide, senaglinide, nateglinide, mitiglinide, GLP-1 and the like), amyrin agonist (e.g. pramlintide and the like), phosphotyrosinphosphatase inhibitor (e.g. vanadic acid and the like) and the like.
Examples of an agent for treating diabetic complications are an aldose reductase inhibitor (e.g., tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidareatat, SK-860, CT-112 and the like), a neurotrophic factor (e.g., NGF, NT-3, BDNF and the like), PKC inhibitor (e.g. LY-333531 and the like), AGE inhibitor (e.g. ALT946, pimagedine, pyradoxamine, phenacylthiazolium bromide (ALT766) and the like), an active oxygen quenching agent (e.g., thioctic acid and the like), a cerebrovascular dilating agent (e.g., tiapride, mexiletene and the like).
An antihyperlipemic agent may for example be a statin-based compound which is a cholesterol synthesis inhibitor (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin and the like), a squalene synthetase inhibitor or a fibrate compound having a triglyceride-lowering effect (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate and the like) and the like.
A hypotensive agent may for example be an angiotensin converting enzyme inhibitor (e.g., captopril, enalapril, delapril and the like) or an angiotensin II antagonist (e.g., losartan, candesartan cilexetil, eprosartan, valsartan, telmisartan, irbesartan, tasosartan and the like) and the like.
An antiobesity agent may for example be a central antiobesity agent (e.g., dexfenfluramine, fenfluramine, phentermine, sibutramine, amfepramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex and the like), a pancreatic lipase inhibitor (e.g., orlistat and the like), xcex23 agonist (e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085 and the like), a peptide-based appetite-suppressing agent (e.g., leptin, CNTF and the like), a cholecystokinin agonist (e.g., lintitript, FPL-15849 and the like) and the like.
A diuretic may for example be a xanthine derivative (e.g., theobromine sodium salicylate, theobromine calcium salicylate and the like), a thiazide formulation (e.g., ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, bentylhydrochlorothiazide, penflutizide, polythiazide, methyclothiazide and the like), antialdosterone formulation (e.g., spironolactone, triamterene and the like), a decarboxylase inhibitor (e.g., acetazolamide and the like), a chlorbenzenesulfonamide formulation (e.g., chlorthalidone, mefruside, indapamide and the like), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like.
A chemotherapeutic agent may for example be an alkylating agent (e.g., cyclophosphamide, ifosfamide and the like), a metabolism antagonist (e.g., methotrexate, 5-fluorouracil and the like), an anticancer antibiotic (e.g., mitomycin, adriamycin and the like), a vegetable-derived anticancer agent (e.g., vincristine, vindesine, taxol and the like), cisplatin, carboplatin, etoposide and the like. Among these substances, 5-fluorouracil derivatives such as furtulon and neofurtulon are preferred.
An immunotherapeutic agent may for example be a microorganism or bacterial component (e.g., muramyl dipeptide derivative, picibanil and the like), a polysaccharide having immune potentiating activity (e.g., lentinan, sizofilan, krestin and the like), a cytokine obtained by a gene engineering technology (e.g., interferon, interleukin (IL) and the like), a colony stimulating factor (e.g., granulocyte colony stimulating factor, erythropoetin and the like) and the like, among these substances, those preferred are IL-1, IL-2, IL-12 and the like.
In addition, an agent whose cachexia improving effect has been established in an animal model or at a clinical stage, such as a cyclooxygenase inhibitor (e.g., indomethacin and the like) [Cancer Research, Vol.49, page 5935-5939, 1989], a progesterone derivative (e.g., megestrol acetate) [Journal of Clinical Oncology, Vol.12, page 213-225, 1994], a glucosteroid (e.g., dexamethasone and the like), a metoclopramide-based agent, a tetrahydrocannabinol-based agent (supra), a lipid metabolism improving agent (e.g., eicosapentanoic acid and the like) [British Journal of Cancer), Vol.68, page 314-318, 1993], a growth hormone, IGF-1, or an antibody against TNF-xcex1, LIF, IL-6, oncostatin M which are cachexia-inducing factors may also be employed concomitantly with a compound according to the present invention.
The possible preferred combinations of the agents for the prevention and/or treatment of the diseases mentioned above are as follows;
(1) an insulin sensitivity enhancing agent, an insulin formulation and a Biguanide;
(2) an insulin sensitivity enhancing agent, a sulfonylurea agent and a Biguanide;
(3) an insulin sensitivity enhancing agent, a sulfonylurea agent and an xcex1-glycosidase inhibitor;
(4) an insulin sensitivity enhancing agent, a Biguanide and an xcex1-glycosidase inhibitor;
(5) an insulin sensitivity enhancing agent, a blood sugar reducing agent and the other kind of agents for treating diabetic complications; and
(6) an insulin sensitivity enhancing agent and any other two kinds of agents mentioned above.
In case that the compound or the composition of the present invention is used in combination with another agent, the amount of each additional agent can be reduced to a range which is safe in light of its adverse effect. Especially, an insulin sensitivity enhancing agent, a biguanide and a sulfonylurea agent can be used in lower dosage than the regular dose. So, adverse effects which may be caused by these agents can be safely avoided. In addition, an agent for treating diabetic complications, an antihyperlipemic agent and a hypotensive agent can also be used in lower dosages, so that adverse effects which may be caused by them can be avoided effectively.
(19) Production Methods
A method for preparing a compound according to the present invention is described below. Since Compounds (I-1) and (I-2) is included in Compound (II), a method for preparing Compound (II) is described below.
Compound (II) according to the present invention may be prepared by a method known per se, such as Method A and Method B shown below as well as analogous methods. 
wherein Z is a hydroxyl group, a halogen atom or a group represented by OSO2R18 wherein R18 is an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms which may be substituted with an alkyl group having 1 to 4 carbon atoms, and other symbols are defined as described above.
In this scheme, an alkyl group having 1 to 4 carbon atoms in xe2x80x9can alkyl group having 1 to 4 carbon atomsxe2x80x9d and xe2x80x9can aryl group having 6 to 10 carbon atoms which may be substituted with an alkyl group having 1 to 4 carbon atomsxe2x80x9d represented by R18 may for example be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, with methyl being preferred.
An aryl group having 6 to 10 carbon atoms in xe2x80x9can aryl group having 6 to 10 carbon atoms which may be substituted with an alkyl group having 1 to 4 carbon atomsxe2x80x9d represented by R18 may for example be phenyl, naphthyl, with phenyl being preferred.
In this method, Compound (III) is reacted with Compound (IV) to produce Compound (II).
When Z is hydroxy group, this reaction may be performed by a method known per se, for example, a method described in Synthesis, page 1 (1981) or analogous methods. Thus, this reaction is performed usually in the presence of an organic phosphorus compound or an electrophilic reagent in a solvent having no adverse effect on the reaction.
An organic phosphorus compound may for example be triphenylphosphine, tributylphosphine and the like.
An electrophilic reagent may for example be diethyl azodicarboxylate, diisopropyl azodicarboxylate, azodicarbonyldipiperazine and the like.
The amounts of an organic phosphorus compound and an electrophilic reagent to be employed were about 1 to about 5 molar equivalents to Compound (IV).
A solvent having no adverse effect on the reaction may for example be an ether such as diethyl ether, tetrahydrofuran, dioxane and the like; a halogenated hydrocarbon such as chloroform, dichloromethane and the like; an aromatic hydrocarbon such as benzene, toluene, xylene and the like; an amide such as N,N-dimethylformamide; a sulfoxide such as dimethyl sulfoxide and the like. These solvents may be employed as a mixture in an appropriate ratio.
The reaction temperature is usually about xe2x88x9250xc2x0 C. to about 150xc2x0 C., preferably about xe2x88x9210xc2x0 C. to about 100xc2x0 C.
The reaction time is about 0.5 to about 20 hours.
When Z is a halogen atom or a group represented by OSO2R18, this reaction is performed by a standard method in the presence of a base in a solvent having no adverse effect on the reaction.
A base may for example be an alkaline metal salt such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate and the like; an amine such as pyridine, triethylamine, N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undeca-7-en and the like; a metal hydride such as potassium hydride, sodium hydride and the like; an alkaline metal alkoxide such as sodium methoxide, sodium ethoxide, potassium t-butoxide and the like.
The amount of a base listed above is preferably about 1 to about 5 molar equivalents to Compound (IV).
A solvent having no adverse effect on the reaction may for example be an aromatic hydrocarbon such as benzene, toluene, xylene and the like; an ether such as tetrahydrofuran, dioxane and the like; a ketone such as acetone, 2-butanone and the like; a halogenated hydrocarbon such as chloroform, dichloromethane and the like; an amide such as N,N-dimethylformamide; a sufoxide such as dimethylsulfoxide and the like. These solvents may be employed as a mixture in an appropriate ratio.
The reaction temperature is usually about xe2x88x9250xc2x0 C. to about 150xc2x0 C., preferably about xe2x88x9210xc2x0 C. to about 100xc2x0 C.
The reaction time is usually about 0.5 to about 20 hours.
Subsequently, Compound (II, R3xe2x95x90OR8) is hydrolyzed if necessary to produce Compound (IIxe2x80x3).
This hydrolyzation may be performed by a standard method, in the presence of an acid or a base, in a water-containing solvent.
An acid may for example be hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid and the like.
A base may for example be an alkaline metal carbonate such as potassium carbonate, sodium carbonate and the like; a metal alkoxide such as sodium methoxide and the like; an alkaline metal hydroxide such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like.
The amount of an acid or a base to be used is usually in excess relative to Compound (II). Preferably, the amount of an acid to be employed is about 2 to 50 equivalents to Compound (II), while the amount of a base to be employed is about 1.2 to about 5 equivalents to Compound (II).
A water-containing solvent may for example be a solvent mixture consisting of water and one or more solvents selected from the group consisting of an alcohol such as methanol, ethanol and the like; an ether such as tetrahydrofuran, dioxane and the like; dimethylsulfoxide and acetone and the like.
The reaction temperature is usually about xe2x88x9220xc2x0 C. to about 150xc2x0 C., preferably about xe2x88x9210xc2x0 C. to about 100xc2x0 C.
The reaction time is usually about 0.5 to about 20 hours.
Compound (II) and Compound (IIxe2x80x3) thus obtained may be isolated and purified by a known separation and purification procedure such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, partition and chromatography and the like.
Compound (III) and Compound (IV) employed as starting materials in Method A described above are known compounds, and, for example, Compound (III) wherein Z is hydroxy group is described in EP-A 710659. Compound (III) is also described in EP-A 629624 (Japanese Patent Application Laid-Open No. 7-53555), WO 98/03505 and the like. Compound (III) may also be prepared by a method analogous to those described in these publications.
Compound (IV) is described for example in Journal fur Praktische Chemie, Vol.311, page 370 (1969); Canadian Journal of Chemistry, Vol.48, page 1948 (1970); Journal of Heterocyclic Chemistry, Vol.25, page 1283 (1988) and the like. Compound (IV) may also be prepared by a method analogous to those described in these publications.
Among Compound (II), a compound wherein R2 is phenyl substituted by an aliphatic hydrocarbon group and the like may be prepared also by Method B shown below. 
wherein W is an aliphatic hydrocarbon group, each optionally substituted aromatic hydrocarbon or aromatic heterocyclic group, and other symbols are defined as described above. xe2x80x9cAn aliphatic hydrocarbon groupxe2x80x9d represented by W may be an aliphatic hydrocarbon group exemplified as a substituent in a hydrocarbon group and a heterocyclic group represented by R1.
Each of an aromatic hydrocarbon group and an aromatic heterocyclic group in xe2x80x9can optionally substituted aromatic hydrocarbon or aromatic heterocyclic groupxe2x80x9d represented by W may be an aromatic hydrocarbon group and an aromatic heterocyclic group each exemplified as a substituent on a hydrocarbon group and a heterocyclic group represented by R1. A substituent on these aromatic hydrocarbon group and aromatic heterocyclic group may be a substituent exemplified as a substituent when a substituent on a hydrocarbon group and a heterocyclic group represented by R1 is a an alicyclic hydrocarbon group, an aromatic hydrocarbon group, an aromatic heterocyclic group or a non-aromatic heterocyclic group.
In this method, Compound (II-1) is reacted with boronic acid compound (V) to produce Compound (II-2).
This reaction is performed by a method known per se such as a method described in Journal of Organic Chemistry, Vol.58, page 2201 (1993) or in Journal of Organic Chemistry, Vol.60, page 1060 (1995), in the presence of a metal catalyst and a base, in a solvent having no adverse effect on the reaction.
A metal catalyst may for example be a palladium metal a nickel metal and the like. A palladium metal catalyst may for example be tris(dibenzylideneacetone)dipalladium, tetrakis(triphenylphosphine)palladium and the like, and a nickel metal catalyst may for example be 1,1xe2x80x2-bis(diphenylphosphino)ferrocene nickel and the like.
A base may for example be an alkaline metal bicarbonate such as sodium bicarbonate; an alkaline metal carbonate such as sodium carbonate, potassium carbonate; an alkaline metal phosphate such as tripotassium phosphate and the like.
The amount of a metal catalyst to be used is about 0.01 to about 1 molar equivalents, preferably about 0.05 to about 0.5 molar equivalents to Compound (II-1).
The amount of a base to be used is about 1 to about 20 molar equivalents, preferably about a to about 10 molar equivalents to Compound (II-1).
A solvent having no adverse effect on the reaction may for example be an aromatic hydrocarbon such as benzene, toluene and the like; an alcohol such as methanol, ethanol and the like; an ether such as tetrahydrofuran, dioxane and the like; water and the like. These solvents may be used in a mixture in an appropriate ratio. The types of the solvents may appropriately be selected depending on the types of the metal catalysts.
The amount of boric acid compound (V) employed is about 1 to about 7 molar equivalents, preferably about 1 to about 5 molar equivalents to Compound (II-1).
The reaction temperature is usually about xe2x88x9220xc2x0 C. to about 150xc2x0 C., preferably about 0xc2x0 C. to about 100xc2x0 C.
The reaction time is about 0.1 to about 24 hours.
Subsequently, Compound (II-2, R3xe2x95x90OR8) is hydrolyzed if desired to produce Compound (IIxe2x80x3-1).
This hydrolyzation may be performed similarly to the hydrolyzation in Method A.
Compound (II-2) and (IIxe2x80x3-1) thus obtained may be isolated and purified by a known separation and purification procedure such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, partition and chromatography and the like.
Compound (II-1) employed as a starting material in Method B described above may for example be produced by Method A described above. Compound (V) is a known compound described in Organic Synthesis, Vol.39, page 3 (1959); Journal of American Chemical Society, Vol.94, page 4370 (1972) and the like. Compound (V) may be prepared also by a method analogous to those described in these publications.
Compound (II) may be produced by [Method C] or [Method D] described below. 
In this method, the reaction between Compound (VI) and Compound (VII) results in Compound (II). This reaction may be performed by a method known per se. Thus, this reaction may be performed in the presence of an acid or a base in a solvent having no effects on the reaction. Such acid includes hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and the like. Such base includes sodium carbonate, potassium carbonate, sodium acetate, (aqueous) ammonia and the like. The amount of an acid or a base to be used is usually about 1 to 10 molar equivalents to Compound (VI). A solvent having no effects on the reaction includes ethers such as tetrahydrofuran, dioxane and the like, alcohols such as methanol, ethanol and the like, as well as dimethylsulfoxide, acetic acid, water and the like. Any of these solvents may be used in combination with each other at an appropriate ratio. The reaction temperature is usually about xe2x88x9250xc2x0 C. to about 150xc2x0 C., preferably about xe2x88x9210xc2x0 C. to about 120xc2x0 C.
Subsequently, if desired, Compound (II) may be hydrolyzed to form Compound (IIxe2x80x3). This reaction may be performed similarly to the hydrolyzation in Method A.
Compound (II) and Compound (IIxe2x80x3) thus obtained may be isolated and purified by a known isolation and purification method such as concentration, concentration under reduced pressure, extraction with a solvent, crystallization, recrystallization, partition, chromatography and the like. 
In this method, the reaction between Compound (VIII) and Compound (IX) results in Compound (II). This reaction may be performed similarly to the reaction between Compound (III) and Compound (IV) in Method A.
Subsequently, if desired, Compound (II) may be hydrolyzed to form Compound (IIxe2x80x3). This reaction may be performed similarly to the hydrolyzation in Method A.
Compound (II) and Compound (IIxe2x80x3) thus obtained may be isolated and purified by a known isolation and purification method such as concentration, concentration under reduced pressure, extraction with a solvent, crystallization, recrystallization, partition, chromatography and the like.
A compound wherein R3 is NR9R10 in Compound (II) may be produced by Method E shown below. 
In this method, Compound (IIxe2x80x3) is amidated to produce Compound (IIxe2x80x2xe2x80x3). This reaction may be performed by a method known per se, i.e. a direct condensation between Compound (IIxe2x80x3) and Compound (X) using a condensation reagent (e.g., dicyclohexylcarbodiimide), or may be performed by an appropriate reaction of a reactive derivative of Compound (IIxe2x80x3) with Compound (X). In such reaction, a reactive derivative of Compound (IIxe2x80x3) includes an acid anhydride, an acid halide (acid chloride, acid bromide), imdazolide, or a mixed acid anhydride (e.g., anhydride with methyl carbonate, ethyl carbonate, isobutyl carbonate, and the like) and the like. For example, when an acid halide is employed, the reaction may be performed in the presence of a base, in a solvent having no effects on the reaction. Such base may for example be triethylamine, N-methylmorpholine, N,N-dimethylaniline, sodium bicarbonate, sodium carbonate, potassium carbonate and the like. Such solvent having no effects on the reaction includes a halogenated hydrocarbon such as chloroform and dichloromethane; an aromatic hydrocarbon such as benzene and toluene; an ether such as tetrahydrofuran and dioxane as well as ethyl acetate and water. Any of these solvents may be used in combination with each other at an appropriate ratio. The amount of Compound (X) to be used is about 1 to 10 molar equivalents to Compound (IIxe2x80x3), preferably about 1 to 3 molar equivalents. The reaction temperature is usually about xe2x88x9230xc2x0 C. to about 100xc2x0 C., and the reaction time ranges from about 0.5 to 20 hours. When a mixed acid anhydride is employed, Compound (IIxe2x80x3) is reacted with chlorocarbonic ester (e.g., methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate) in the presence of a base (e.g., triethylamine, N-methylmorpholine, N,N-dimethylaniline, sodium bicarbonate, sodium carbonate, potassium carbonate) and further reacted with Compound (X). The amount of Compound (X) to be used is about 1 to 10 molar equivalents to Compound (IIxe2x80x3), preferably about 1 to 3 molar equivalents. The reaction temperature is usually about xe2x88x9230xc2x0 C. to about 100xc2x0 C., and the reaction time ranges from about 0.5 to 20 hours.
Compound (IIxe2x80x2xe2x80x3) thus obtained may be isolated and purified by a known isolation and purification method such as concentration, concentration under reduced pressure, extraction with a solvent, crystallization, recrystallization, partition, chromatography and the like.
Compound (VI) used as a starting material in Method C may be produced by a method known per se, such as a method described in Journal of Organic Chemistry, Vol.36, page 3836 (1971) or a method analogous thereto.
Compound (IX) used as a starting material in Method D may be produced by Method F shown below. 
This method is performed similarly to the reaction between Compound (III) and Compound (IV) in Method A. The xe2x80x94YH moiety in Compound (XI) may be protected prior to the condensation reaction and then deprotected after the reaction. A protective group which may be employed are benzyl group, methoxymethyl group, a silyl group (e.g., trimethylsilyl group, t-butyldimethylsilyl group) and the like.